EP3439640B1 - Nanopartikel zur arzneimittelabgabe zur behandlung von knochenerkrankungen - Google Patents
Nanopartikel zur arzneimittelabgabe zur behandlung von knochenerkrankungen Download PDFInfo
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- EP3439640B1 EP3439640B1 EP17779909.5A EP17779909A EP3439640B1 EP 3439640 B1 EP3439640 B1 EP 3439640B1 EP 17779909 A EP17779909 A EP 17779909A EP 3439640 B1 EP3439640 B1 EP 3439640B1
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- nps
- bone
- nanoparticles
- cancer
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- A61K47/6937—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol the polymer being PLGA, PLA or polyglycolic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
- A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Definitions
- compositions for treating cancer in at least one bone of a subject using nanoparticles encapsulating, or conjugated to, an anti-cancer agent as defined in the appended set of claims.
- compositions for treating cancer cells in a bone in a subject using nanoparticle encapsulating, or conjugated to, a RANKL inhibitor as defined in the appended set of claims.
- the nanoparticle are neutral or nearly neutral in charge (e.g., zeta potential between -5 and +5 mV) and less than 250 nm in hydrodynamic diameter on average, determined in water by dynamic light scattering with NICOMP 380 ZLS (Particle Sizing Systems, Santa Barbara, CA) (e.g. have an average diameter between 100 and 200 nm), as defined in the appended set of claims.
- Bone is a common site for metastasis in a number of human cancers (e.g., breast and prostate), in large part because of the relatively slow blood flow in bone marrow and the presence of adhesion receptors on bone marrow capillary endothelial cells that support cancer cell localization in the bone. These characteristics, together with the fact that bone marrow is an environment rich in growth factors and cytokines, all promote progression of bone metastasis [1, 2].
- prostate cancer presents with a significantly high incidence: -70-80% of patients develop bone metastases. The 5-year survival rate of patients with bone metastases is very low compared with those in whom the disease is localized (20% vs. 100%).
- compositions for treating cancer in at least one bone of a subject using nanoparticles encapsulating, or conjugated to, an anti-cancer agent as defined in the appended claims.
- the nanoparticle are, neutral or nearly neutral in charge (e.g., zeta potential between -5 and +5 mV) and less than 250 nm in diameter on average, determined in water by dynamic light scattering with NICOMP 380 ZLS (Particle Sizing Systems, Santa Barbara, CA) (e.g. have an average diameter between 100 and 200 nm).
- compositions may be used in methods of treating cancer (not comprised by the appended claims in view of Art. 54(3) EPC), said methods comprising: administering a composition to a subject, wherein the composition comprises nanoparticles encapsulating and/or conjugated to a drug, wherein the nanoparticles are neutral or nearly neutral in charge and less than 250 nm in diameter on average, wherein the subject has cancer cells in at least one bone, wherein the drug is an anti-cancer agent, and wherein the administering kills at least some of the cancer cells in the at least one bone.
- compositions as defined in the appended claims comprising: nanoparticles encapsulating and/or conjugated to a drug, wherein the nanoparticles are neutral or nearly neutral in charge and less than 250 nm in diameter on average, and wherein the drug is an anti-cancer agent.
- the nanoparticles comprise poly (D,L-lactide-co-glycolide (PLGA) and a surface polymer, wherein said surface polymer comprises poly (vinyl alcohol).
- PLGA D,L-lactide-co-glycolide
- the nanoparticles are neutral and nearly neutral in charge, e.g. the nanoparticles have a zeta potential between -5 and +5 mV (e.g., -5, -4, -3, -2, -1, 0, +1, +2, +3, +4, or +5 mV)or the nanoparticles have a zeta potential between -3 and +3 mV.
- the nanoparticles are less than 250 nm in hydrodynamic diameter on average, determined in water by dynamic light scattering with NICOMP 380 ZLS (Particle Sizing Systems, Santa Barbara, CA), e.g. the nanoparticles have an average diameter of about 100 to about 250 nm (e.g., 100 ... 150 ... 200 nm).
- the cancer cells are selected from the group consisting of: bone cancer cells, osteosarcoma cells, chondrosarcoma cells, Ewing's sarcoma cells, fibrosarcoma cells, prostate cancer cells, breast cancer cells, lung cancer cells, thyroid cancer cells, and kidney cancer cells.
- the anti-cancer agent is selected from: an anticancer monoclonal antibody of binding fragment thereof; an anticancer small molecule; and a combination of the anticancer monoclonal antibody or the binding fragment thereof and the anticancer small molecule.
- the nanoparticles further encapsulate and/or are conjugated to, a RANKL (receptor activator of nuclear factor-kappa B ligand) inhibitor.
- the RANKL inhibitor is selected from the group consisting of osteoprotegerin (OSG), an anti-RANKL antibody, or binding fragment thereof.
- the RANKL inhibitor comprises denosumab.
- compositions for treating cancer in at least one bone of a subject using nanoparticles encapsulating, or conjugated to, an anti-cancer agent as defined in the appended claims.
- the nanoparticle are neutral or nearly neutral in charge (e.g., zeta potential between -5 and +5 mV) and less than 250 nm in diameter on average, determined in water by dynamic light scattering with NICOMP 380 ZLS (Particle Sizing Systems, Santa Barbara, CA) (e.g. have an average diameter between 100 and 200 nm).
- biodegradable NPs that effectively localize to bone marrow to improve NP-mediated anticancer drug delivery to sites of bone metastasis to inhibit cancer progression and prevent bone loss.
- IV intravenous
- NPs with a neutral surface charge were more effective in localization to and retention in marrow than anionic or cationic NPs and
- a single dose of drug-loaded neutral NPs e.g., PTX-NPs
- the nanoparticles should be neutral or nearly neutral in charge (e.g., a zeta potential between -5 and +5 mV) and be less than 250 in average diameter (e.g., 100-200 nm's in average diameter).
- Nanoparticles may be composed of biodegradable polymers (e.g., as shown in Examples 1 and 2).
- the nanoparticles comprise poly(lactide-co-glycolide) (PLGA), as defined in the claims.
- the anti-cancer drug or RANKL inhibitor may be formulated as a solid lipid nanoparticle (see, e.g., U.S. Patent 8,980,864 ).
- a solid lipid nanoparticle may be spherical with an average diameter between 10 to 250 nm, or 100-200 nm.
- SLN possess a solid lipid core matrix that can solubilize lipophilic molecules and may be stabilized with surfactants and/or emulsifiers.
- the lipid nanoparticle may be a self-assembly lipid-polymer nanoparticle (see Zhang et al., ACS Nano, 2008, 2 (8), pp 1696-1702 ).
- the NPs may be formulated by a single oil-in-water emulsion solvent-evaporation method (e.g., with conditions generally optimized to obtain NPs of similar size and neutral or nearly neutral charge).
- NPs with neutral or nearly neutral surface charge are formulated by modulating the amount of surface polymer (e.g., PVA) associated with NPs or using the cationic surfactant (e.g., CTAB) in combination with a surface polymer (e.g., PVA, as in previously described procedures [21, 22]).
- Surface polymer include, but are not limited to, ethylene oxide/propylene oxide diblock and triblock poly(ethylene glycol), pluronics and tetronics, acrylic acid and alkyl acrylate, fatty acids, sodium lauryl sulfate, and alpha olefin sulfonate.
- the surface-associated emulsifier is that which remains associated with NPs at the interface despite repeated washing. The emulsifier remains because of the anchoring and integration of the hydrophobic segment of the emulsifier (polyvinyl acetate in the case of PVA or the acyl chain in the case of CTAB) with the polymer matrix at the interface.
- the role of the residual PVA on physical and biological properties has been determined with respect to PLGA-NPs [23-26].
- the nanoparticles comprise or may be formed (e.g., primarily) from the biodegrable polymer poly(D,L-lactide-co-glycolide (PLGA).
- the biodegradable polymer comprises a poly(lactide-co-glycolide).
- the nanoparticle may be generally as shown in Figure 11 , which shows a generally spherical nanoparticle with a core matrix made of biodegradable polymer with drug in it, and an outer Surface Polymer layer.
- the surface is modified with a surface polymer (e.g., PVA).
- PVA surface polymer
- a surface polymer and a cationic surfactant e.g., CTAB, cethyl trimethylammonium bromide
- the polymer used to make the nanoparticles may be biodegradable polymer (e.g., one which is brokendown in the body and are cleared) and are biocompatible. Such polymer may be hydrophobic.
- the polymers may be long-chain polymers that breakdown in the presence of water, releasing the content slowly.
- the polymers may be linear or branched with hydrophobic and/or hydrophilic units.
- the polymers may be linear and/or branched or block co-polymers with combination of different polymer segments, functionalized or esterified.
- the surface polymers may have a hydrophobic chain and hydrophilic chain.
- PVA polyvinyl acetate which hydroponic and part of polyvinyl acetate is hydrolyzed to make polyvinyl alcohol which is hydrophilic.
- the surface polymers may have a balance of hydrophobic and hydrophilic segments so that they anchor onto the surface of the polymer at the interface (e.g., an acetate segment is buried into the matrix whereas alcohol segment is outside of the nanoparticles).
- Advanced-stage prostate cancer often metastasizes to bone but becomes incurable due to poor biodistribution of intravenously administered anticancer drugs within bone.
- Bisphosphonates are currently used to reduce the risk of skeleton-related events and to ameliorate bone pain, but they do not improve survival.
- Injected drugs or drug-loaded nanocarriers conjugated to bone-seeking agents remain inefficient in treating bone metastasis.
- Provided herein e.g., as a therapy for bone metastasis
- NP nanoparticle
- PEGylated NPs because of their hydrophilic surface, remain in the circulation rather than efficiently extravasating through the fenestrations in bone-marrow capillaries.
- the approach provided herein provides non-PEGylated NPs with characteristics (size, charge, and surface composition) so that following their intravenous administration, these NPs do extravasate through the openings of the marrow's sinusoidal capillaries.
- NPs described herein may be employed to deliver a RANKL inhibitor to bone.
- the RANKL inhibitor may be denosumab (DNmb) is a monoclonal antibody that binds to receptor activator of nuclear factor- ⁇ B ligand (RANKL).
- RANKL Over expression of RANKL in the bone microenvironment drives the vicious destructive cycle of progression of bone metastasis and bone resorption.
- Both ani-cancer and RANKL inhibitors may be employed together.
- DNmb is used as a targeting ligand against RANKL and docetaxel are combined with the NPs.
- NPs herein which effectively localize to bone, and the combination of DNmb and TXT with their complementary mechanism of action, are used to inhibit progression of bone metastasis and prevent bone loss (see Figure 9 ).
- the 5-year survival rate is much lower when cancer metastasizes to bone (-20% vs. 100% if localized).
- bone is less perfused than other organs (cardiac output 7% to bone vs. 30% to liver), intravenously administered chemotherapeutics cannot achieve therapeutic levels at bone metastatic sites.
- New approaches for drug delivery to bone are needed to effectively treat bone metastases.
- nanocarriers for drug delivery to treat bone metastasis remains an under-researched area; most approaches focus on treating soft-tissue tumors.
- Bone marrow has sinusoidal capillaries with intercellular clefts as wide as 170 nm between endothelial cells; however, despite their long systemic circulation time and small size (smaller than the capillary fenestrations in bone marrow), PEGylated nanoparticles (NPs) cannot effectively extravasate into bone.
- NPs PEGylated nanoparticles
- the anti-cancer drug with the NPs is docetaxel (TXT).
- TXT is more potent than PTX and is the drug of choice to treat metastatic prostate cancers.
- the combination of DNmb and TXT (or other combination of RANKL inhibitor and anti-cancer agent) is employed because of their complementary roles in preventing bone resorption and cancer progression.
- DNmb is employed as a targeting ligand for the NPs against RANKL in a metastatic bone micro-environment.
- an RANKL inhibitor e.g., Denosumab (DNmb)
- DNmb Denosumab
- osteoprotegerin (OPG) produced by osteoblast binds to RANKL to maintain a balance but within the tumor bone environment, OPG production is downregulated by factors such as parathyroid hormone-related peptide, and other factors produced and secreted by tumor cells (IL-6, prostaglandin E2, TNF, and macrophage-colony stimulating factor), shifting the balance further towards greater RANKL availability which stimulates osteoclastogenesis; b) growth factors produced by differentiated osteoclasts that promotes cancer cell growth and proliferation to drive further progression of bone metastasis; c) the effect of RANKL produced by prostate cancer cells that promotes transformation of osteoblast to osteoclasts; and d) migration of circulating prostate cancer cells to bone marrow as RANKL is considered as chemo-attractant.
- factors such as parathyroid hormone-related peptide, and other factors produced and secreted by tumor cells (IL-6, prostaglandin E2, TNF, and macrophage-colony stimulating factor), shifting the balance further
- a microtubule inhibitor can induce cancer cell death in the marrow that can be synergistic with RANKL inhibitor-NPs ( Figure 9 ).
- RANKL inhibitor- NPs e.g., DNmb-nano
- anti-cancer-NPs e.g., TXT-nano
- Bone marrow possesses sinusoidal capillaries with intracellular clefts between endothelial cells, and some of these clefts are as wide as 170 nm ( Fig. 10 ) (and see refs. 43,44).
- the NPs may be constructed with some of all of the following characteristics: 1) small enough to pass through sinusoidal capillaries of bone marrow and be retained in the bone marrow; 2) large enough so that they do not pass through the sinusoidal capillaries of the liver or kidney; 3) remain in circulation for sufficient time to extravasate through sinusoidal capillaries of bone marrow; 4) reduce interactions with proteins to avoid clearance by the organs of the RES; and 5) non-pegylated to they may remain in circulation rather than extravasate through bone marrow capillaries.
- the NPs' surface may be modulated to reduce the uptake of NPs by Kupffer cells to avoid hepatic uptake as well as minimize their interactions with complement-activating proteins to reduce clearance by the organs of the reticuloendothelial system (RES). Further, for therapeutic efficacy, sustained retention of the extravasated NPs in the bone marrow at the metastatic tumor site is also important.
- RES reticuloendothelial system
- NPs are modified with hydrophilic polymers such as polyethylene glycol (PEG; PEGylated NPs) or pluronics to sustain their time in the circulation.
- PEG polyethylene glycol
- PEGylated NPs hydrophilic polymers
- PEG polyethylene glycol
- pluronics to sustain their time in the circulation.
- EPR enhanced permeation and retention
- Modification of NPs with PEG/pluronics has been shown to improve biocompatibility of NPs, reduce particle aggregation, and PEG provides easy and flexible chemistry for conjugation to ligands for targeting.
- PEGylated NPs have been shown useful in other applications (e.g., they diffuse more efficiently through the mucus barrier than non-PEGylated NPs).50,51
- PEGylated/pluronic modified NPs are not effective in extravasating into the bone marrow.52
- Several studies have reported that despite a long systemic circulation time and size smaller than
- NPs with an anionic, neutral or cationic surface charge were formulated by modulating the amount of PVA associated with NPs or using the cationic surfactant cetyltrimethylammonium bromide (CTAB) in combination with PVA as per the previously described procedures.64,65
- CTAB cetyltrimethylammonium bromide
- the surface-associated emulsifier remains associated with the NP surface, despite repeated washing of NPs. This condition occurs because of the anchoring and integration of the hydrophobic segment of the emulsifier (polyvinyl acetate in the case of PVA or an acyl chain in the case of CTAB) with the polymer matrix at the interface.
- Various additives may be employed to modulate the release of drugs (e.g., hydrophobic drugs, such as U-86983) from the NPs described herein.
- drugs e.g., hydrophobic drugs, such as U-86983
- DMTA L-tartaric acid dimethyl ester
- MW 178
- DMTA is inert and soluble in both organic and water solvents, is compatible with PLGA, and is effective in creating pores, thus acting as a plasticizer.
- the rate of drug release from matrix depends on the percent of DMTA (5%-20% w/w) added into the polymer mass. At 10% DMTA, the drug release rate was ⁇ 5 times the rate without it. Therefore the NPs may comprise 3-35% DMTA, or similar agent, to modulate the release of drugs form the NPs. For example, this approach may be used to modulate the TXT-release rate from PLGA-NPs.
- DMTA 5%-20% w/w polymer mass
- NPs with RANKL inhibitors may be employed.
- DNmb-NPs are formulated using PLGA with DMTA (or other poreforming agent) added. Because of its poreforming ability, DMTA incorporated into PLGA polymer (1:9 w/w) allows free diffusion of the acidic oligomers (polylactic and polyglycolic acids) that form as a result of polymer degradation.
- sustained release enzymes superoxide dismutase, SOD and catalase, CAT
- this formulation composition is effective for sustained release of other proteins (vascular endothelial growth factor; basic fibroblast growth factor) in active form, with 12% cumulative release in 24 hrs, 60% release in 5 wks and 100% in 9 wks.
- NPs described herein contain or are conjugated to an anti-cancer agent, as defined in the appended claims.
- Table 5 provides a list of exemplary anti-cancer agents that may be employed with the nanoparticles described herein.
- NPs biodegradable nanoparticles
- Such NPs localize to bone marrow thereby improve NP-mediated anticancer drug delivery to sites of bone metastasis, thereby inhibiting cancer progression and preventing bone loss.
- these small neutral NPs demonstrated greater accumulation in bone within metastatic sites than in normal contralateral bone as well as colocalization with the tumor mass in marrow.
- PTX-NPs paclitaxel
- anionic PTX-NPs slowed the progression of bone metastasis.
- neutral PTX-NPs prevented bone loss, whereas animals treated with the rapid-release drug formulation Cremophor EL (PTXCrEL) or saline (control) showed >50% bone loss.
- PTXCrEL Cremophor EL
- saline control
- Poly (D,L-lactide- co -glycolide) (PLGA; 50:50, inherent viscosity of 0.26-0.54 dL/g) was purchased from LACTEL Absorbable Polymers (Birmingham, AL).
- Poly (vinyl alcohol) (PVA; 87-90% hydrolyzed, mol wt 30,000-70,000), sucrose, Cremophor EL (CrEL) and cetyltrimethylammonium bromide (CTAB) were purchased from Sigma-Aldrich (St. Louis, MO).
- NIR Near-infrared
- SDB5700 was obtained from H.W. Sands Corp. (Jupiter, FL). Chloroform was obtained from Fisher Scientific (Pittsburgh, PA).
- Paclitaxel (PTX) was purchased from LC Laboratories (Woburn, MA).
- NPs were formulated by a single oil-in-water emulsion solvent-evaporation method, but conditions were optimized to obtain NPs of similar size but different surface charges. Briefly, NPs with either an anionic, neutral or cationic surface charge were formulated by modulating the amount of PVA associated with NPs or using the cationic surfactant CTAB in combination with PVA, as per our previously described procedures [21, 22] (see Supplemental Material). It is important to note that the surface-associated emulsifier is that which remains associated with NPs at the interface despite repeated washing.
- the emulsifier remains because of the anchoring and integration of the hydrophobic segment of the emulsifier (polyvinyl acetate in the case of PVA or the acyl chain in the case of CTAB) with the polymer matrix at the interface.
- the role of the residual PVA on physical and biological properties was determine for PLGA-NPs [23-26].
- PLGA NPs of larger size than those used above were also formulated and tested for their localization in bone (see further below).
- NPs were loaded with NIR dye SDB5700.
- This dye has previously been evaluated for in vivo imaging and biodistribution of NPs in breast [27] and prostate [22] xenograft models.
- the dye offers several advantages, including a stable signal (even after repeated laser exposure), a high-fluorescence yield, no background signal, and only an insignificant amount of dye leaching from NPs because of the hydrophobic nature of the dye and its low loading (0.1% w/w polymer weight) [22].
- PTX-loaded NPs were formulated to determine therapeutic efficacy.
- the hydrodynamic diameter and ⁇ -potential of NPs were determined in water by dynamic light scattering with a NICOMP 380 ZLS (Particle Sizing Systems, Santa Barbara, CA).
- NPs were characterized for surface-associated PVA, surface morphology, and size using atomic force microscopy (AFM) [22].
- PTX loading in NPs was determined by extracting the drug from NPs using methanol.
- PTX release from NPs was carried out in double diffusion chambers under sink conditions as described previously [28].
- PTX levels in samples were analyzed by high-performance liquid chromatography (see further below for detailed methods used for formulation and characterization of NPs).
- NPs Biodistribution of NPs.
- a single dose of a 100- ⁇ L suspension of NIR dye-loaded NPs (30 mg/mL) in saline was injected via tail vein into each mouse, and animals were imaged at different time points post injection with a Maestro EX Imaging system (PerkinElmer, Waltham, MA) using blue and NIR filters set at exposure times of 500 ms and 1200 ms, respectively.
- a Maestro EX Imaging system PerkinElmer, Waltham, MA
- To quantify relative signal intensity due to NPs localized in tibia the region of interest (ROI) covering the entire tibia was used.
- ROI region of interest
- PC-3M-luc cells obtained from the NIH were cultured in RPMI 1640 supplemented with 10% FBS at 37 °C and 5% CO2. Bone metastasis was induced as described by Park et al. [29].
- mice under ketamine/xylazine anesthesia were injected with 4 ⁇ 105 PC-3M-luc cells in 20 ⁇ L PBS intraosseously in the lumen of the right tibia, then monitored for induction of bone metastasis and its progression using changes in bioluminescence signal intensity (photons per second per square centimeter steradian; [p/sec/cm2/sr]) and micro-computed tomography (micro-CT) to determine bone loss.
- bioluminescence animals were imaged 15 min following intraperitoneal injection of luciferin (200 mg/kg; VivoGlo TM Luciferin, Promega, Madison, WI) using the IVIS ® Lumina II (PerkinElmer).
- the IVIS ® Lumina II was used to co-register the bioluminescence signal of cancer cells and the fluorescence signal of the dye-loaded NPs in metastasized bone.
- limbs resected at the head of the femur were imaged using an in vivo micro-CT for preclinical procedures (eXplore Locus RS Micro-CT, GE Healthcare, London, ON, Canada).
- the micro-CT images were acquired using an X-ray tube (80 kV, 490 ⁇ A) for an exposure time of 1.8 seconds.
- the detector bin was set to 1 ⁇ 1 spatial resolution, providing a full resolution of 20 ⁇ m. Images were acquired for every degree of rotation, creating 360 raw data projections. These projections were corrected, unwarped and reconstructed using GE's proprietary reconstruction algorithms to create a full three-dimensional reconstruction of the scanned specimen.
- Flow cytometry analysis of bone marrow cells To determine cellular uptake of NPs in bone marrow, animals without tumor were injected with NIR dye-loaded NPs (3 mg in 100 ⁇ L saline) and euthanized 24 hours following injection. Their femurs were resected and flushed with saline to recover the bone marrow. The collected marrow was incubated in red blood cell lysis buffer (Sigma-Aldrich) for 10 min, centrifuged to recover nucleated cells, and washed twice with saline. Flow cytometry was performed on nucleated cells in the red channel to determine the percentage of cells with dye-loaded NPs (BD FACSAria II, BD Biosciences, San Jose, CA).
- red blood cell lysis buffer Sigma-Aldrich
- the PTX dose was calculated from the standard dose of 175 mg/m2 used in prostate cancer patients. Tumor growth was monitored by weekly bioluminescence imaging of cancer cells using IVIS ® . At 5 weeks post treatment, animals were euthanized, and both hind legs were harvested. The difference in the weight of the contralateral leg and the tumor-bearing leg was used to calculate tumor burden [30, 31].
- NPs of different surface charges and size 90 mg PLGA was dissolved in 3 mL chloroform; this was then added to 12 mL of either 1% w/v PVA solution to form anionic NPs or 2% w/v PVA to form neutral NPs.
- a polymer solution was emulsified into a 1% PVA solution containing 4 mM cetyltrimethylammonium bromide (CTAB). The polymer and PVA solutions were vortexed for 30 sec, and then sonicated using a probe sonicator (XL 2015 Sonicator Ultrasonic processor, Misonix, Inc., Farmingdale, NY) for 3 minutes in an ice bath.
- CTAB cetyltrimethylammonium bromide
- the resulting emulsion was passed through a high-pressure homogenizer (EmulsiFlex C5; Avestin, Ottawa, ON, Canada) for 10 cycles between 5,000-10,000 psi to reduce particle size.
- a high-pressure homogenizer EmulsiFlex C5; Avestin, Ottawa, ON, Canada
- the emulsion was sonicated for 5 minutes as above, but without homogenization.
- the emulsions were stirred overnight in a fume hood and the formed NPs were recovered by ultracentrifugation at 30,000 rpm (Rotor 50.2Ti, Beckman L80, Beckman Coulter, Inc., Brea, CA) at 4 °C for 30 min.
- NPs were washed twice with water, resuspended in 3% sucrose solution in water prior to lyophilization for 2 days at -48 °C, 3.5 Pa (FreeZone 4.5, Labconco Corp., Kansas City, MO).
- 100 ⁇ g SDB5700 was added to the polymer solution to formulate anionic and neutral NPs; 200 ⁇ g SDB5700 was used to formulate cationic NPs.
- the amount of dye required for formulating cationic NPs was higher than that used for anionic or neutral NPs because a fraction of the added dye in the polymer solution partitioned into the CTAB micelles formed in the external aqueous phase.
- NPs nanoparticles
- the mean hydrodynamic diameter of nanoparticles (NPs) was determined by dynamic light scattering with a Nicomp 380 ZLS (Particle Sizing Systems, Santa Barbara, CA). A 100 ⁇ g/mL suspension of NPs in water was sonicated on ice for 30 seconds, and a 50 ⁇ L aliquot was added to a borosilicate glass disposable culture tube (Kimble Chase, Vineland, NJ) for particle sizing. The same NP suspensions were used to measure the zeta potential in the dual-phase analysis and current mode at a scattering angle of -14°. Surface morphology of NPs was determined by atomic force microscopy on air-dried NPs coated onto silicon wafers.
- the silicon wafers (Ted Pella, Inc., Redding, CA) were cleaned by immersion into a mixture of H2O/H2O2/NH4OH (4:1:1 volume) at 80 °C for 5 minutes, rinsed with ultrapure water and dried under continuous N2 flow. A 100- ⁇ L aliquot of freshly prepared NPs suspension in water was applied onto the cleaned silicon wafer inclined at an angle of 25 ° to ensure uniform spread of the NPs and dried in a dust-free environment.
- a BioScope II Atomic Force Microscope (Bruker Nano Surfaces, Santa Barbara, CA) using a 125- ⁇ m-long silicon probe with resonance frequency of ⁇ 300 Hz and a tip radius ⁇ 10 nm (Ted Pella, Inc., Redding) was used for imaging in tapping mode at a scan speed of 0.5 Hz and a set-point ratio of 1.0 at a resolution of 512 ⁇ 512 pixels. Images were flattened using a second-order flattening routine in Nanoscope software version 7.30 (Bruker Nano Surfaces, Santa Barbara, CA).
- PVA polyvinyl alcohol
- Absorbance of the Iodine-PVA complex formed was measured at 690 nm using a spectrophotometer (DU 640B, Beckman Coulter, Brea, CA).
- a standard plot for PVA was prepared in the concentration range of 0-1000 ⁇ g/mL PVA in water.
- Neutral-NPs show 38% and 18% more residual PVA than anionic and cationic NPs, respectively.
- PTX loading in NPs was determined by extracting PTX from NPs by incubating 2 mg NPs in acetonitrile for 48 hours at 4 °C. Drug release from NPs was carried out in double diffusion chambers separated by a 0.1 ⁇ m membrane filter (Millipore, Billerica, MA). Sink condition was achieved using 0.1% (v/v) Tween-80 (Sigma, St. Louis, MO) in phosphate-buffered saline (PBS) containing 0.1% sodium azide as a preservative. The donor chamber of each diffusion chamber was filled with 2 mL buffer containing 2 mg NPs; the receiver chambers contained 2 mL release buffer without NPs.
- PBS phosphate-buffered saline
- Filled diffusion chambers were rotated on an orbital shaker at 100 rpm at 37 °C. The entire content of receiver chambers was collected at different time points and replaced with fresh release buffer. Collected samples were frozen at -80 °C and lyophilized; PTX from each sample was extracted with 300 ⁇ L acetonitrile. The amount of PTX in each sample was determined by high-performance liquid chromatography (Shimadzu Scientific Instruments, Columbia, MD) with a Kinetex C-18 column (Phenomenex, Torrance, CA) using acetonitrile/water (50:50) as the mobile phase; injection volume was 25 ⁇ L. PTX was detected with an ultraviolet detector at 228 nm at an elution time of 5.1 minutes. A standard plot was constructed for PTX in the concentration range of 0-1000 ⁇ g/mL. PTX extracted from NPs to determine drug loading was analyzed using the above method.
- NP formulation and characterization All small NP formulations showed a similar hydrodynamic diameter and size distribution (polydispersity index) but varied in their surface charge ( ⁇ -potential) ( Table 1, Fig. 1 ).
- AFM images of the NPs showed their spherical shape, irrespective of surface charge ( Fig. 1A ).
- Mean NP diameter as determined by AFM was smaller than the hydrodynamic diameter measured in water using the dynamic light scattering technique ( Table 1 ).
- the larger NPs had a mean hydrodynamic diameter of 321 nm (range, 248-460 nm; polydispersity index, 0.1) and ⁇ -potential of -15 mV.
- PTX loading in NPs was 6.4 ⁇ 0.3% w/w and demonstrated 28% cumulative drug release over 7 weeks ( Fig. 1C ).
- Biodistribution of NPs with different surface charges was carried out in normal mice (without tumor) to determine which formulation of NPs would show better localization and retention in bone marrow.
- the imaging data showed differences in the biodistribution of NPs, particularly over time, as a function of their charge.
- Immediately following injection (2 min) all formulations of NPs primarily showed localization in the liver; however, this biodistribution changed as time went on ( Fig. 2A ).
- Fig. 3A the accumulation of neutral NPs in tibia was 2.5-fold higher than anionic or cationic NPs.
- animals were euthanized and dissected at 24 hrs post injection of neutral NPs to visualize their biodistribution in other bones. Besides localization in the tibia and sternum, neutral NPs were seen in all the bones. Based on signal intensity, a greater accumulation of neutral NPs was seen in the pelvis and vertebral column than in the ribs and craniofacial bones ( Fig. 3B ). In the vertebral column, neutral NPs were seen more in thoracic than in lumbar vertebrae ( Fig. 3C ).
- a close-up image of the tibia showed localization of neutral NPs in the marrow rather than in the bone tissue ( FIG. 3D ), which was further confirmed from flow cytometry analysis of the marrow, which showed 90% of the nucleated cells with NPs ( Fig. 3E , F ).
- an excised section of the femur also showed localization of NPs in the marrow (image not shown).
- the whole-body skeleton imaging showed an approximately 7-fold greater accumulation of small neutral NPs in bones than large NPs ( Fig. 6 ).
- Nanoparticle localization in metastasized bone Bioluminescence and micro-CT images confirmed induction of intraosseous tumor in the lumen of the tibia within 1 week post inoculation of bone marrow with PC-3M-luc cells ( Fig. 4A ,B ). The imaging data demonstrated that neutral NPs following IV administration show two-fold greater accumulation in the tibia with metastasis than in the normal contralateral tibia ( Fig. 4C ,D ). Ex vivo imaging of the harvested bone from these animals further confirmed greater localization of neutral NPs in the metastasized tibia than in the normal contralateral tibia ( Fig. 4E ). In addition, co-localization of bioluminescence signal of cancer cells with fluorescence signal of NPs ( Fig. 4F ) indicated the delivery of neutral NPs to the tumor mass in the bone marrow.
- PTX-NPs At 3 weeks post treatment, animals that had received PTX-NPs still demonstrated a lower tumor burden: 61% and 143% lower than untreated controls or those treated with PTX-CrEL, respectively ( Fig. 5A ,B ).
- Tumor burden calculated from the weight difference between the limb with tumor and the contralateral normal limb at the end of the study (5 weeks post treatment), shows significantly lower tumor burden in animals treated with PTXNP than in untreated saline controls or the animals treated with PTX-CrEL (P ⁇ 0.05) ( Fig. 5C ). Since anionic and cationic NPs have similar bone marrow uptake and retention ( Fig. 3 ), we tested PTX-loaded anionic NPs for inhibition of bone metastasis.
- NP-based therapies progress in the field of cancer nanomedicine is evident from the entry of several NP-based therapies and an increasing number of ongoing clinical studies for treating different types of cancers [34, 35].
- efficacy of NPs has been attributed to either better drug delivery directly to cancerous tissue and/or reduced toxicity compared with drugs alone.
- most of these approaches have been focused on treating primary soft-tissue, highly vascularized, solid tumors. Effective treatment for tumors that arise from advanced-stage cancer metastasis, the major cause of cancer-related mortality, still remains a challenge.
- neutral PTX-NPs are demonstrably effective in slowing the progression of bone metastasis and inhibiting bone loss in an intraosseous model of bone metastasis. Since neutral NPs have a prolonged circulation time compared with anionic and cationic NPs and since they are also smaller than the opening of the intercellular clefts of bone marrow endothelial cells, neutral NPs are more effective in localizing in the marrow ( Fig. 3 ).
- Neutral NPs have been reported to have a lower propensity to interact with proteins, which could be the reason for their relatively longer time in the circulation than charged NPs [36]. Furthermore, while the present invention is not limited to any particular mechanism, and an understanding of the mechanism is not necessary to practice the invention, it believed that surface-associated PVA, which is present in greater amounts on neutral NPs than on anionic or cationic NPs, could have played a role in sustaining the retention time of the NPs in the bloodstream.
- PVA is a copolymer comprising both hydrophobic and hydrophilic portions.
- a hydrophobic polyvinyl acetate segment integrates within the PLGA-NP matrix, whereas a hydrophilic segment forms an outer corona that could also reduce opsonization [36]. It has been previously shown that a significant fraction of PVA remains associated with the NPs over several days when incubated in PBS at 37 oC [37]. This finding means that the NPs' surface composition would be maintained for a period of time following their IV injection, which is important, since the surface characteristics of the NPs determine their bio-distribution.
- the general strategy used to keep NPs in the circulation is to prevent their recognition by circulating monocytes and their subsequent clearance by the organs of the reticuloendothelial system (RES), particularly the liver and spleen.
- RES reticuloendothelial system
- the liver signal due to NPs, particularly for neutral NPs drops over time ( Fig. 2A ). This drop suggests that the major fraction of these NPs become contained in the vascular compartment of the liver and are not taken up by Kupffer cells or hepatocytes.
- the liver receives 30% of cardiac output. Therefore, the initial high fluorescence signal seen in the liver could be due to the NPs carried with the blood flow to the liver [38].
- NPs taken up by Kupffer cells degrade slowly, whereas those taken up by hepatocytes are excreted through the hepatic biliary duct into the gut. This process is known to occur more rapidly for cationic than anionic NPs [39] but has not yet been reported for neutral NPs.
- the relatively more rapid drop in the liver signal seen in this example in animals injected with neutral NPs than cationic or anionic NPs suggests that neutral NPs are better at escaping uptake by Kupffer cells or hepatocytes than anionic or cationic NPs ( Fig. 2A ,B ).
- the neutral NPs in this example seem to have avoided sequestering by the liver through their reduced opsonization, thus preventing their uptake by circulating monocytes and subsequent clearance by the organs of the RES, such as liver and spleen. Furthermore, the size of neutral NPs ( ⁇ 150 nm hydrodynamic diameter, 112 nm in the dry state, measured using AFM) is greater than the opening of the fenestrations ( ⁇ 75 nm) in the liver sinusoidal endothelial cell lining [40] but smaller than those in the bone marrow endothelial cell capillaries (170 nm) [16, 17, 41].
- neutral NPs appear to achieve the above balance in two ways: first, by escaping the liver and remaining in the circulation, but then (following their passage through the bone's sinusoidal capillaries) becoming sequestered in the marrow because of the marrow's comparatively sluggish blood flow [42] ( Fig. 2B and 3A ).
- Table 1 a quite uniform size distribution
- a fraction of the smaller NPs present in the formulation could have passed through the sinusoidal capillaries of the liver.
- hepatic uptake of these NPs could not be completely prevented but might be further minimized by controlling particle size within a certain narrow range.
- NPs are modified with hydrophilic polymers such as polyethylene glycol (PEG; PEGylated NPs) or pluronics to extend their time in the circulation.
- PEG polyethylene glycol
- EPR enhanced permeation and retention
- PEGylated/ pluronicmodified NPs cannot effectively extravasate into the bone marrow [44].
- uptake of these NPs into bone marrow remains negligible [45]. It is possible that steric hindrance due to the surface-associated PEG/pluronic could have prevented extravasation of these NPs into bone marrow.
- NPs In addition to charge, the size of NPs is known to influence their localization in bone marrow.
- the data in this Example show that neutral NPs have about a 7-fold greater localization in bone marrow than larger NPs (hydrodynamic diameter ⁇ 150 nm vs. ⁇ 320 nm), signifying that the openings in the intercellular clefts between endothelial cells lining the bone marrow, which are ⁇ 170 nm, regulate the delivery of NPs to the bone marrow [16, 17].
- Currently, patients with bone metastasis are treated with bisphosphonates to reduce the risk of deleterious skeleton-related events and to ameliorate bone pain, as bisphosphonates can inhibit bone resorption [47].
- bisphosphonates indirectly slow the progression of bone metastasis [48] by inhibiting osteoclast-mediated bone resorption and thereby the release of growth factors necessary to promote cancer cell growth and differentiation and subsequent tumor formation in bone [49].
- a recent review of data from different clinical studies shows no statistically significant improvement in survival of bisphosphonatetreated patients compared with placebo controls [50].
- bisphosphonates show dose-limiting toxicities, with chronic use, they cause osteonecrosis of the jaws, considered to be a consequence of their effect on circulating endothelial progenitor cells, interfering in the normal process of angiogenesis and vasculogenesis required to maintain healthy tissue [51].
- NPs localize to and are retained in marrow, where bone metastasis initiates and progresses, rather than to bone itself. Furthermore, the increased accumulation of NPs in bone that has been invaded by cancer compared with normal bone could be due to increased permeability of the blood-bone microvasculature as a result of tumor growth. Since NPs also localize into the metastatic tumor mass, the therapy is effective in suppressing the progression of bone metastasis ( Fig. 5 ).
- Fig. 5D One important finding of this example was that a single-dose IV injection of neutral PTX-NPs prevented bone loss ( Fig. 5D ), suggesting the NPs' efficacy in delivering drug to marrow to prevent invasion of PC-3 cells in bone matrix.
- PTX is known to inhibit receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclastogenesis by causing mitotic arrest of osteoclastic precursor cells, thus inhibiting the progression of bone metastasis to pathological osteolysis [52].
- RTKL nuclear factor-kappa B ligand
- PLGA-based NPs typically demonstrate a triphasic release profile: the first release phase is mediated via diffusion of the drug at the interface, followed by a second, steady-release phase during which an insignificant amount of the encapsulated drug is released, and the third phase, in which the polymer matrix degrades, releasing the remaining encapsulated drug.
- the first release phase is mediated via diffusion of the drug at the interface, followed by a second, steady-release phase during which an insignificant amount of the encapsulated drug is released, and the third phase, in which the polymer matrix degrades, releasing the remaining encapsulated drug.
- a considerable fraction of PTX is still entrapped within the NPs.
- NP albumin-bound (nab) PTX despite having smaller particle size ( ⁇ 130 nm) than the openings of the bone marrow capillary fenestrations ( ⁇ 170 nm), has in fact been shown to increase the incidence of metastasis, including to bones, in an animal model of breast cancer metastasis [57].
- nab-PTX is a fast-release drug formulation and has a clearance profile similar to that of PTX-CrEL [58].
- Prolonged circulation time is considered critical to give the NPs sufficient time to localize into soft-tissue tumors, as NPs often extravasate through the leaky tumor vasculature due to the EPR effect [66].
- neutral NPs could very well be effective in treating both primary tumors and those that have metastasized to bone.
- TXT-NPs docetaxel-loaded nanoparticles
- TXT is generally the preferred drug used for treating prostate cancer because it is more potent than PTX.
- PTX is generally the preferred drug used for treating prostate cancer because it is more potent than PTX.
- NPs loaded with TXT using the same protocol used for PTX (Example 1 above), considering that both the drugs have similar chemical structures and physical properties, particularly their hydrophobicity based on octanol-water partition coefficient. It was found that the PLGA polymer used for making PTX-NPs was not compatible with TXT, as there was phase separation of the drug from the polymer, resulting in TXT crystallization and large aggregate formation during the NP formation.
- PTX and TXT have quite different solid-state solubility profile in polymers.
- TXT-NPs were tested for their efficacy in a small number of animals to ensure their efficacy in inhibiting the progression of bone metastasis.
- an intraosseous model of prostate cancer was used where PC-3-Luc cells were injected into the tibia.
- PC-3_Luc cells (5 ⁇ 105 in 20 ⁇ L) were injected into the lumen of the right tibia of nude mice. Change in bioluminescence signal intensity was measured.
- the treatment (12mg/kg TXT equivalent dose TXT-NPs) was administered through tail vein at one-week post-tumor inoculation whereas controlled group did not receive any treatment.
- the data shows the inhibition of bone metastasis following a single-dose intravenous injection of TXT -NPs as compared to untreated control ( Figure 8 ).
- TXT and PTX have similar structures and physical properties, they have different solid-state solubility with polymers which significantly impact the selection of polymer for formulating NPs for each drug.
- formulated TXT-NPs are effective in vitro in cell culture and in vivo in bone metastasis model of prostate cancer.
- a single-dose intravenous injection of TXT-NPs is effective in inhibiting the progression of bone metastasis.
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Claims (17)
- Zusammensetzung, die Nanopartikel umfasst, die ein Arzneimittel einkapseln und/oder mit diesem konjugiert sind, zur Verwendung bei der Behandlung von Krebs bei einem Subjekt,wobei die Nanopartikeli) nicht PEGyliert sind undii) eine neutrale oder nahezu neutrale Ladung aufweisen undiii) im Durchschnitt einen hydrodynamischen Durchmesser von weniger als 250 nm aufweisen, bestimmt in Wasser durch dynamische Lichtstreuung mit NICOMP 380 ZLS (Particle Sizing Systems, Santa Barbara, CA),wobei das Subjekt Krebszellen in mindestens einem Knochen hat,wobei das Arzneimittel ein Anti-Krebs-Mittel ist,wobei die Behandlung mindestens einige der Krebszellen in dem mindestens einen Knochen abtötet undwobei die Nanopartikel Poly(D,L-lactid-co-glycolid (PLGA) und ein Oberflächenpolymer umfassen,wobei das Oberflächenpolymer Poly(vinylalkohol) umfasst.
- Zusammensetzung zur Verwendung nach Anspruch 1, wobei die Nanopartikel des Weiteren ein porenbildendes Mittel umfassen.
- Zusammensetzung zur Verwendung nach Anspruch 1, wobei das Anti-Krebs-Mittel Docetaxel (TXT) oder Paclitaxel (PTX) ist.
- Zusammensetzung zur Verwendung nach Anspruch 1, wobei die Nanopartikel klein genug sind, um durch die Öffnungen der Knochensinusoidkapillaren in einem Knochen des Subjekts zu extravasieren und somit im Knochenmark lokalisiert zu werden.
- Zusammensetzung zur Verwendung nach Anspruch 1, wobei die Nanopartikel einen durchschnittlichen Durchmesser von etwa 100 bis 200 nm aufweisen.
- Zusammensetzung zur Verwendung nach Anspruch 1, wobei die Krebszellen ausgewählt sind aus der Gruppe bestehend aus: Knochenkrebszellen, Osteosarkomzellen, Chondrosarkomzellen, Ewing-Sarkomzellen, Fibrosarkomzellen, Prostatakrebszellen, Brustkrebszellen, Lungenkrebszellen, Schilddrüsenkrebszellen und Nierenkrebszellen.
- Zusammensetzung zur Verwendung nach Anspruch 1, wobei das Anti-Krebs-Mittel ausgewählt ist aus: einem monoklonalen Antikörper gegen Krebs oder einem Bindungsfragment davon; einem kleinen Molekül gegen Krebs; und einer Kombination aus dem monoklonalen Antikörper gegen Krebs oder dem Bindungsfragment davon und dem kleinen Molekül gegen Krebs.
- Zusammensetzung zur Verwendung nach Anspruch 1, wobei die Nanopartikel des Weiteren einen RANKL-Inhibitor (receptor activator of nuclear factor-kappa B ligand) einkapseln und/oder mit diesem konjugiert sind.
- Zusammensetzung zur Verwendung nach Anspruch 8, wobei der RANKL-Inhibitor ausgewählt ist aus der Gruppe bestehend aus Osteoprotegerin (OSG), einem Anti-RANKL-Antikörper oder einem bindenden Fragment davon.
- Zusammensetzung umfassend: Nanopartikel, die ein Arzneimittel einkapseln und/oder mit diesem konjugiert sind,wobei die Nanopartikeli) nicht PEGyliert sind undii) eine neutrale oder nahezu neutrale Ladung aufweisen undiii) im Durchschnitt einen hydrodynamischen Durchmesser von weniger als 250 nm aufweisen, bestimmt in Wasser durch dynamische Lichtstreuung mit NICOMP 380 ZLS (Particle Sizing Systems, Santa Barbara, CA),wobei das Arzneimittel ein Anti-Krebs-Mittel ist undwobei die Nanopartikel Poly(D,L-lactid-co-glycolid (PLGA) und ein Oberflächenpolymer umfassen,wobei das Oberflächenpolymer Poly(vinylalkohol) umfasst.
- Zusammensetzung nach Anspruch 10, wobei die Nanopartikel des Weiteren ein porenbildendes Mittel umfassen.
- Zusammensetzung nach Anspruch 10, wobei das Anti-Krebs-Mittel Docetaxel (TXT) oder Paclitaxel (PTX) ist.
- Zusammensetzung nach Anspruch 10, wobei die Nanopartikel klein genug sind, um durch die Öffnungen der Knochensinusoidkapillaren in einem Knochen des Subjekts zu extravasieren und somit im Knochenmark lokalisiert zu werden.
- Zusammensetzung nach Anspruch 10, wobei die Nanopartikel einen durchschnittlichen Durchmesser von etwa 100 bis 200 nm aufweisen.
- Zusammensetzung nach Anspruch 1, wobei das Anti-Krebs-Mittel ausgewählt ist aus:
einem monoklonalen Antikörper gegen Krebs oder einem Bindungsfragment davon; einem kleinen Molekül gegen Krebs; und einer Kombination aus dem monoklonalen Antikörper gegen Krebs oder dem Bindungsfragment davon und dem kleinen Molekül gegen Krebs. - Zusammensetzung nach Anspruch 10, wobei die Nanopartikel des Weiteren einen RANKL-Inhibitor (receptor activator of nuclear factor-kappa B ligand) einkapseln und/oder mit diesem konjugiert sind.
- Zusammensetzung nach Anspruch 16, wobei der RANKL-Inhibitor ausgewählt ist aus der Gruppe bestehend aus Osteoprotegerin (OSG), einem Anti-RANKL-Antikörper oder einem bindenden Fragment davon.
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